DESCRIPTION(Provided by Applicant): Accumulating evidence has demonstrated that the products of the wnt, frizzled [fzd], secreted frizzled- Irelated protein [SFRP] and LDL receptor-related protein [LRP1 gene families play a critical role in the ]development and maintenance of joints and bones. Consequently, polymorphisms of these genes that alter protein expression or function are potential biomarker candidates for osteoarthritis [OA] susceptibility and progression. The overall goal of this project is to confirm this hypothesis. Several prior genetic studies of familial OA have mapped a major susceptibility locus to chromosome 2q31, a region that encodes FRZB [also known as SFRP3], a SFRP family member that antagonizes wnt signaling. Preliminary experiments from our laboratory, performed in collaboration with John Loughlin of the University of Oxford, have demonstrated that a specific mutation of the FRZB gene is significantly more common in both familial and sporadic female patients with hip OA, than in female controls. In transfecfion experiments, the mutated FRZB genes have diminished wnt-inhibitory function compared to wild type genes. Excessive wnt signaling can increase subchondral bone density and possibly chondrocyte metabolic activity at the bonecartilage junctions. Indeed, other preliminary experiments using surface enhanced laser desorption and ionization mass spectrometric analysis of OA sera have revealed increased concentrations of anionic proteins with molecular masses corresponding to several wnt-associated proteins. Accordingly, we postulate that the FRZB mutants are biomarkers for hip OA in women, and that they alter the serum concentrations of wnt-regulated proteins. To test this hypothesis, we aim [1] to confirm the association of the observed FRZB mutations in an additional series of female patients with hip OA characterized by Nancy Lane and Michael Nevitt at UCSF, [2] to assess the association between the FRZB mutants and increased hip bone density in these women, and [3] to compare the patterns of expression, and the levels, of wnt-inducible proteins in the blood of OA patients with defined FRZB polymorphisms, and of controls, by surface-enhanced laser desorption and ionization mass spectrometry, and by immunoassay. The results of these studies will both contribute to, and will utilize, the resources of the OA biomarker consortium.